MXPA98006121A - Use of imitazolidin-2,4-diona substituted compounds as analgesi - Google Patents

Abstract

The use of substituted imidazolidin-2,4-dione compounds in analgesic is revealed

Description

USE OF SUBSTITUTE COMPOUNDS OF IMIDAZOLIDIN-2, 4-DIONA AS ANALGESICOS Description of the Invention The invention relates to the use of substituted imidazolidin-2,4-dione compounds to prepare medicaments for the treatment of pain. Pain is a subjective experience of the senses that is composed of a sensor component and an affective component. The physiological aspects of the origin of pain include the reception of any physical-chemical stimulus in an intensity that potentially threatens the tissues with activation of the so-called nociceptors, special uni- or polymodal nociceptors of the primary ascending nervous cords of high threshold. By observing the pathophysiological aspects of the origin of pain in general, all parts of the nociceptive system may be modified: reception through nocisensors, transmission in the spinal plane, perception, awareness and assimilation in the supraspinal plane. Plastic modifications and chronifications may occur due to disorders in the afferent system, but also due to disturbed perception and assimilation, as well as due to disorders in the descendant system, endogenous controller of pain inhibition. In the case of chronic or neuropathic pain, among other things, the sensitization of nociceptors is carried out through endogenous or exogenous substances. In the case that the influence of the stimulus is prolonged or, by means of the disturbance of the integrity of the nociceptor, a secondary and also central sensitization can then be presented in the spinal plane. These phenomena are known primarily in the case of chronic inflammation processes, for example in the case of rheumatoid arthritis. Tissue and transmitter hormones (histamine, serotonin, prostaglandin, interleukin 1) inflammation promoters that shed local inflammation cells in the nocisensor region can lead to sensitization of nociceptors with a reduced stimulus threshold and increased activity spontaneous, being that prolonged inflammation processes with a permanent influx of stimulus eventually lead to the regulation of adaptive processes, also in the spinal and supraspinal plane. The substituted imidazolidin-2,4-dione compounds and their immunomodulatory activity are known from the German patent application 19540027.5. It was now surprisingly found that these compounds also possess an antinociceptive activity, which can not be derived from the immunomodulatory and antivasculitic activities hitherto known.

Accordingly, the invention relates to the use of substituted imidazolidin-2,4-dione compounds of the formula I wherein R1 signifies C? -6-alkyl or C3-6-cycloalkyl and, R2 signifies C? -6-alkyl, phenyl, - (CH2)? _3-phenyl or - (CH2)? -4- COOR5 or, R1 and R2 j signify - (CH2) 4-6-, - (CH2) 2-0-CH2) 2-o R3 is H, C? _5-alkyl or - (CH2)? -4-COOR, R4 is a heteroaromatic of the group with the formulas R5 represents C? -3-alkyl, R6 signifies H, C? -alkyl phenyl or benzyl and, R7 signifies H, C? _4-alkyl or trifluoromethyl, to prepare a medicament for the treatment of pains. The substituted imidazolidin-2,4-dione compounds of the formula I are preferably used with R 1 Ci-e-alkyl, R 2 C 6 -alkyl, phenyl or - (CH 2) α 3 -phenyl or, R 1 and R 2 together - (CH2) 4-6- or and RH or C? -4-alkyl and, especially those compounds of the formula I are preferred with R1 C? -4-alkyl, R2 C3.5-alkyl or phenyl or, R1 and R2 j untos - (CH2) 5- or and R3 H or C? _4-alkyl. The use of the substituted imidazolidin-2,4-dione compounds of the formula I with R 4 thiazol-2-yl or pyrazin-2-yl is particularly preferred. At least one substituted imidazolidin-2-dione compound of the formula I can be used as a single active substance or in combination with another or more, additional active substances for the preparation of an analgesic. Particularly suitable additional active substances are selected from at least one of the group of opioids, tramadol material and non-opioid analgesics. Examples of the opioids are morphine, hydromorphone, codeine, oxycodone, dihydrocodeine, dextropropoxyphen, buprenorphine, levometadon, fentanyl, sufentanil, as well as the pharmaceutical salts of the active substances mentioned above. The tramadol material comprises tramadol (1RS; 2RS) -2- [(dimethylamino) methyl] -l- (3-methoxyphenyl) cyclohexanol)], oxide-N-tramadol, O-demethyltramadol, the tramadol derivatives disclosed in German patent applications DE 4426245, 195 25 137.7 , 196 09 847.5 and 197 10 628.5, as well as the pharmaceutical salts of the aforementioned tramadol materials, in racemic or enantiomeric form. Suitable non-opioid analgesics are, for example, carboxylic acids and esters of carboxylic acids, such as salicylates, arylacetic acids and arylpropionic acids, for example acetylsalicylic acid, diclofenac, naproxen, ketoprofen, and ibuprofen, ketoenol heterocyclic hydrogenated opioids, such as oxicams and pyrazolidinediones, for example non-hydrogenated non-opioid piroxicam and tenoxicam, anilines and pyrazolinones, for example paracetamol and metamizole, as well as non-opioid pyridylcarbamates, for example flupirtine and benzoxazocin, for example nefopam. In the case of the use according to the invention of a substituted imidazolidin-2,4-dione compound of the formula I in combination with another analgesic, the proportion by weight of both active substances is generally between 1: 0.01 and 1:25 The pain-inhibiting effect of the substances a to be employed according to the invention is independent of whether the pain comes from an inflammation. In addition, the antinociceptive activity of the substances to be employed according to the invention does not correlate with TNFa inhibition. The antinociceptive activity of the substituted imidazolidin-2,4-dione compounds of the formula I can not be explained by the known antinociceptive mechanisms, such as μ opioid receptor agonism, inhibition of monoaminergic reabsorption or with an interaction with a receptor such as adenosine , adrenoreceptor a / β, GABA, galanin, glutamate / NMDA, histamine, somatostatin, tachykinin, VIP or NPY, or with one of the following calcium channel systems, potassium, MAO, NO-synthetase, protein kinase or enzyme / second messenger. The possibility that the inhibitory effect of pain is due to an interaction with endogenous NGF (Nervous Growth Factor) can not be excluded. The substituted imidazolidin-2, -dione compounds of the formula I are preferably used for the preparation of medicaments for the treatment of chronic pain conditions. Chronic pain states, ie pain states of chronic inflammation and chronically neuropathic states, occur for example in the cases of rheumatism, secondary inflammatory osteoarthrosis, back pain, tension headaches, trauma, herpes zoster and trigeminal neuralgia. For the preparation of the analgesics, the compounds to be used according to the invention are used together with vehicles, fillers, solvents, diluents, colorants and / or binders. The choice of the auxiliary substances as well as the amounts to be used depend on the form of administration intended for the analgesic to be prepared, whether oral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal or local. For the oral application, preparations in the form of matrix tablets, coated tablets, multilayer tablets, chewable tablets, dragees, capsules, granules, drops, juices or syrups are suitable for parenteral application, topical and by inhalation, solutions, suspensions, dehydrated preparations of easy reconstitution, as well as the aspersions. The compounds according to the invention in dissolved form in a reservoir, in a carrier sheet or in a plaster, optionally with the addition of means for promoting skin penetration, are examples of suitable forms of percutaneous application. From the processing forms to be used orally or percutaneously, the compounds according to the invention can be released in a delayed manner. They are usually applied per unit dose of 5 to 500 mg, preferably 10 to 200 mg of at least one substituted imidazolidin-2,4-dione compound of the formula I. EXAMPLES The pain inhibitory activity of the substances to be used according to the invention was determined in three test models. The following substituted imidazolidin-2,4-dione compounds were employed according to the process described in German patent application 19540027.5: 5-ethyl-5-phenyl-3-pyrazin-2-yl-imidazolidin-2, 4-disna (compound 1) 5-ethyl-5-phenyl-3-thiazol-2-yl-imidazolidin-2,4-dione (compound 2) 3-thiazol-2-yl-l, 3-diaza-spiro [4.5] decan -2,4-dione (compound 3) 5-isobutyl-5-methyl-3-thiazol-2-yl-imidazolidin-2, -dione (compound 4) 3-thiazol-2-yl-l, 3-diaza-spiro [4.4] benzononan-2,4-dione (compound 5) l-propyl-3-thiazol-2-yl-l, 3-diaza-spiro [4.5] decan-2,4-dione (compound 6) 5, 5-dipropyl-3-thiazol-2-yl -imidazolidin-2,4-dione (compound 7) 1. Randall-Selitto test For the determination of the antinociceptive activity in vivo in the Randall-Selitto test (Arch. Int.Pharmacodyn.Ther.III, 409 (1957)), by injecting 0.1 ml of a 20% suspension of baking yeast, injected into a rat hind paw, an edema was induced that after 4 hours led to a mecanohyperalgesia accentuates. By increasing the pressure (0-450 g / mm2) with a punch (0.2 mm diameter of the tip) on the inflamed hind leg of the rat, pain followed and, as a measurement value, the pressure was determined to which the vocalization reaction of the rat occurred. The animals that had not vocalized up to the maximum admitted pressure were considered totally analgesic. The administration of the test substances was carried out intraperitoneally in a dosage of 10 ml / kg and 30 minutes before the Randall-Selitto measurement. The results of the test are represented as MPE (maximum possible effect) in%, according to the formula: [Measurement value after the substance - measurement value before the substance] / [Maximum value - measurement value before the substance] x 100. Calculations of the mean effective dose ED5o were carried out according to the linear regression, the credibility regions were calculated according to Litchfield and Wilcoxon (J. Phrmacol.Exp.Ther.95, 99 (1949 )). 2. Formalin test To check for activity according to the indication in the case of chronic pains, a formalin test was chosen (Pain 4, 161 (1977); Pain 30, 103 (1987)). For this purpose, animal pain reactions were recorded by observation as complex behavioral patterns after the injection of formalin in a rat or mouse hind paw, and were quantified according to an assessment system for the test of the effectiveness of the animal. compound 3. This test is not limited to the verification of spinal alignment reactions or supra-spinally controlled individual reactions, but encompasses the modified complex behavior of the entire animal. For compound 3 an ED50 value of 35.6 mg / kg for direct analgesic activity and an ED50 value of 33.3 mg / kg for analgesic inhibition in the second chronic phase and, in the mouse, an ED50 value of 31.8 was determined in the rat. mg / kg for direct analgesic activity and an ED50 value of 32.8 mg / kg for analgesic inhibition in the second chronic phase. 3. Hot plate test To check the activity in the case of acute thermal stimulus not caused by inflammation, the spinal / supraspinal nociceptive reaction time in the hot plate test arrangement was investigated (J. Pharmacol. 133, 400 (1944)). For compound 3, an ED5o value of approximately 100 mg / kg i.p was determined in the mouse. for activity against direct hyperalgesiathermic.

Claims (4)

1. CLAIMS Use of substituted i-idazolidin-2,4-dione compounds of the formula I wherein R1 signifies C? -6-alkyl or C3-6-cycloalkyl and, R2 signifies C? _6-alkyl, phenyl, - (CH2)? _3-phenyl or - (CH2)? -4-COOR5 or, R1 and R2 together mean - (CH2) 4-6- / - (CH2) 2-0-CH2) 2-?
2. R3 is H, C? -5-alkyl or - (CH2)? _4-COOR5, R4 is a heteroaromatic of the group with the formulas
3. R represents C? -3-alkyl, R6 signifies H, C? -4-alkyl phenyl or benzyl and, R7 signifies H, C? -4-alkyl or trifluoromethyl, to prepare a medicament for the treatment of pains. Use according to claim 1, characterized in that the substituted imidazolidin-2,4-dione compounds of the formula I are used with R 1 Ci-e-alkyl, R 2 C 6 -alkyl, phenyl or - (CH 2) )? - 3-phenyl or, R1 and R2 together - (CH2) 4_6- or and R H or C? -5-alkyl. Use according to one or both of claims 1 to 2, characterized in that the substituted imidazolidin-2,4-dione compounds of the formula I are used with R 1 C 4 -4 alkyl, R 2 C 3 5 alkyl or phenyl or, R1 and R2 together - (CH2) 5- or and R 3 H or C
4. 4 -4 alkyl. Use according to one or more of claims 1 to 3, characterized in that the substituted imidazolidin-2,4-dione compounds of the formula I are used with R4 thiazol-2-yl or pyrazin-2-yl. Use according to one or more of claims 1 to 4, characterized in that at least one substituted imidazolidin-2,4-dione compound of the formula I is used together with at least one active substance selected from at least one of groups of opioids, tramadol materials and non-opioid analgesics. Use according to one or more of claims 1 to 5, characterized in that substituted imidazolidin-2,4-dione compounds of the formula I are used for the preparation of a medicament for the treatment of chronic pain.